Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia (original) (raw)

Nature volume 365, pages 65–69 (1993)Cite this article

Abstract

THE microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospho-lipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent _M_r of 88K (refs 1–3). It is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine4. The large subunit of MTP was not detectable in four unrelated subjects with abetalipoproteinaemia5, a rare autosomal recessive disease characterized by a defect in the assembly or secretion of plasma lipoproteins that contain apolipo-protein B (ref. 6). We report here the isolation and sequencing of complementary DNA encoding the large subunit of MTP. A comparison of this sequence to corresponding genomic sequences from two abetalipoproteinaemic subjects revealed a homozygous frameshift mutation in one subject and a homozygous nonsense mutation in the other. The results indicate that a defect in the gene for the large subunit of MTP is the proximal cause of abetalipopro-teinaemia in these two subjects, and that MTP is required for the secretion of plasma lipoproteins that contain apolipoprotein B.

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Authors and Affiliations

  1. Department of Metabolic Diseases, Bristol-Myers Squibb, Princeton, New Jersey, 08543-4000, USA
    Daru Sharp, Laura Blinderman, Bernadette Kienzle, Beverly Ricci, Karen Wager-Smith, Richard E. Gregg, David A. Gordon & John R. Wetterau
  2. Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, 45267, USA
    Kelly A. Combs & Cleris M. Gil
  3. Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco, California, 94143, USA
    Christoph W. Turck
  4. U327 Institut National de la Sante et de la Recherche Médicale, Faculté de Médicine Xavier Bichat, Paris, 75018, France
    Marie-Elizabeth Boumas
  5. Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
    Daniel J. Rader
  6. Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, Gif-sur-Yvette, 91198, France
    Lawrence P. Aggerbeck

Authors

  1. Daru Sharp
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  2. Laura Blinderman
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  3. Kelly A. Combs
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  4. Bernadette Kienzle
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  5. Beverly Ricci
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  6. Karen Wager-Smith
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  7. Cleris M. Gil
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  8. Christoph W. Turck
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  9. Marie-Elizabeth Boumas
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  10. Daniel J. Rader
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  11. Lawrence P. Aggerbeck
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  12. Richard E. Gregg
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  13. David A. Gordon
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  14. John R. Wetterau
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Sharp, D., Blinderman, L., Combs, K. et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia.Nature 365, 65–69 (1993). https://doi.org/10.1038/365065a0

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